title: Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development.
abstract: Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
authors.affiliation: Discovery Chemistry, ‡Discovery Technologies, §Discovery Oncology, ∥Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Ding
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Tina M
authors.initials: TM
authors.lastname: Ross
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Chu
authors.forename: David
authors.initials: D
authors.lastname: Bartkovitz
authors.forename: Frank
authors.initials: F
authors.lastname: Podlaski
authors.forename: Cheryl
authors.initials: C
authors.lastname: Janson
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.forename: Zoran M
authors.initials: ZM
authors.lastname: Filipovic
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D062366:para-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; C586849:RG7388; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; D051736:Proto-Oncogene Proteins c-mdm2